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Biomedical subjects

J Christian Virchow

Publications and source records attributed to J Christian Virchow.

At least 19 recordsLinked to original sources
PubMed2006

Maternal nerve growth factor serum levels in the perinatal period.

Neurotrophins, such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), are potent modulators of neuronal and immune function, and have been implicated recently in diseases associated with pregnancy. In contrast to serum BDNF, which is reportedly suppressed in the perinatal period, regulation of NGF in the perinatal period is unknown. In this study, serum NGF concentrations were measured in 40 pregnant (follow-up: 30th and 37th week of gestation, 1 week and 8 weeks after childbirth) and 40 non-pregnant women. Maternal NGF serum levels did not differ significantly from controls (median: 7.6 pg NGF/ml serum) neither before nor after childbirth, although there was a trend towards increased NGF concentrations at the 37th week of gestation (median: 12.5 pg NGF/ml serum) and 1 week after childbirth (median: 11.6 pg NGF/ml serum). There was no association of maternal NGF with 17beta-estradiol, progesterone, dehydroepiandrosterone sulfate (DHEAS) and cortisol concentrations in maternal serum, or maternal depression, as measured by the Edinburgh Postnatal Depression Scale (EPDS). In the non-pregnant control group, NGF serum concentrations were negatively correlated with the number of days since the first day of the menstrual cycle (r=-0.32, p<0.05). In conclusion, NGF is not altered during normal pregnancy on a systemic level. In addition, NGF displays a different regulation compared with BDNF during the menstrual cycle.

Adult↗
PubMed2006

Dendritic cell subsets in human bronchoalveolar lavage fluid after segmental allergen challenge.

BACKGROUND: Dendritic cells control pulmonary immune reactions. Characteristics of dendritic cells in human bronchoalveolar lavage fluid (BALF) after allergen challenge are unknown. METHODS: 7 patients with allergic asthma (median 23 years, range 19-25 years) underwent segmental challenge and were lavaged 10 min and 24 h after challenge. Dendritic cell subsets and surface markers in BALF and in peripheral blood were analysed using four-colour flow cytometry. RESULTS: Plasmacytoid dendritic cells (pDCs, median 0.06%, range 0.01-0.08%) and myeloid dendritic cells (mDCs, median 0.47%, range 0.27-0.87%) were detectable in BALF from control segments. CD1a-positive dendritic cells in BALF were identified as a subpopulation of mDCs. Both pDCs (median 0.56%, range 0.09-1.83%) and mDCs (median 1.82%, range 0.95-2.29%) increased significantly in BALF 24 h (p = 0.018 compared with the control segments for pDCs and mDCs), but not 10 min, after allergen challenge. The percentage increase in pDCs was higher than that of mDCs after allergen challenge, as reflected by an enhanced pDC:mDC ratio after allergen challenge. In peripheral blood, there was a significant decrease in mDCs (p = 0.038) and a trend to a decrease in pDCs (p = 0.068) 24 h after allergen challenge. Analysis of dendritic cell surface molecules showed that after allergen challenge, BALF dendritic cells have a less mature phenotype compared with BALF dendritic cells from control segments. CONCLUSION: Using a comprehensive strategy to analyse dendritic cell subsets in human BALF, we have shown for the first time that both myeloid and plasmacytoid dendritic cells accumulate in the airway lumen after allergen challenge in patients with asthma.

Adult↗
PubMed2006

Granzyme B, a novel mediator of allergic inflammation: its induction and release in blood basophils and human asthma.

Histamine, leukotriene C4, IL-4, and IL-13 are major mediators of allergy and asthma. They are all formed by basophils and are released in particularly large quantities after stimulation with IL-3. Here we show that supernatants of activated mast cells or IL-3 qualitatively change the makeup of granules of human basophils by inducing de novo synthesis of granzyme B (GzmB), without induction of other granule proteins expressed by cytotoxic lymphocytes (granzyme A, perforin). This bioactivity of IL-3 is not shared by other cytokines known to regulate the function of basophils or lymphocytes. The IL-3 effect is restricted to basophil granulocytes as no constitutive or inducible expression of GzmB is detected in eosinophils or neutrophils. GzmB is induced within 6 to 24 hours, sorted into the granule compartment, and released by exocytosis upon IgE-dependent and -independent activation. In vitro, there is a close parallelism between GzmB, IL-13, and leukotriene C4 production. In vivo, granzyme B, but not the lymphoid granule marker granzyme A, is released 18 hours after allergen challenge of asthmatic patients in strong correlation with interleukin-13. Our study demonstrates an unexpected plasticity of the granule composition of mature basophils and suggests a role of granzyme B as a novel mediator of allergic diseases.

Antibodies, Monoclonal↗
PubMed2006

The course of allergen-induced leukocyte infiltration in human and experimental asthma.

BACKGROUND: Although the timing of allergen-induced bronchoconstriction is well defined, there is little information about the kinetics of allergen-induced leukocyte infiltration in asthma and its comparability between human and animal models of asthma. OBJECTIVE: To investigate systematically allergen-induced leukocyte infiltration into the airway lumen in human and experimental asthma by using bronchoalveolar lavage. METHODS: Patients with allergic asthma were lavaged at different time points as long as 1 week after segmental allergen challenge. Allergen-sensitized mice were lavaged as long as 3 weeks after allergen challenge. Differential cell counts, lymphocyte subsets, and cytokines were assessed in bronchoalveolar lavage fluid. RESULTS: In both models, neutrophil infiltration was a relatively early event (maximum: 18 hours after challenge). In contrast, eosinophil infiltration peaked 42 hours (human model) to 4 days (mouse model) after allergen challenge, paralleled by an IL-5 peak in this period. There were elevated macrophage counts over a period of several days after allergen challenge in both models. Lymphocytes (predominantly CD4+ T cells) peaked 18 hours after challenge in the human model, but not until 2 weeks after challenge in the murine model. CONCLUSION: Early neutrophil accumulation (within hours after challenge) and delayed eosinophil accumulation (within days after challenge) in the airway lumen are common features of allergen-induced airway inflammation, whereas lymphocyte kinetics are dependent on the asthma model. CLINICAL IMPLICATIONS: Similarities in the infiltration kinetics of granulocytes after allergen challenge suggest a common role for these cells in asthma, whereas the presumed orchestration of allergic inflammation by lymphocytes appears to differ between the models.

Adult↗
PubMed2006

[Therapy-resistant asthma--a distinct phenotype?].

While most patients respond well to conventional antiasthmatic therapy as outlined in current guidelines, a small percentage, however, have severe disease which is relatively or completely unresponsive to inhaled as well as oral medications. These patients who often have a long-standing "career" in asthma are frequently labeled steroid-resistant or difficult-to-control but this group of patients is not well defined. It is likely that a number of mechanisms contribute to therapy-resistant asthma such as socioeconomic status, mental disturbances but also characteristics of the individual subgroups within the syndrome of asthma such as aspirin-exacerbated airway disease or intrinsic asthma. A thorough and systematic approach is required in the work-up of these patients which sometimes involves repeated evaluations to determine that asthma and not other diseases such as chronic obstructive pulmonary disease (COPD), emphysema, gastroesophageal reflux, congestive heart failure and many others which can mimic asthma are present. Issues relating to compliance with prior or future therapies are warranted and doctor-patient communication should be checked. A meticulous search for possible triggers such as cigarette smoking, occupational allergens and comorbid conditions should be included in the work-up. High-dose combination therapy including frequent bursts or maintenance therapy with systemic corticosteroids is often necessary. Alternative therapies such as methotrexate and other immunosuppressants should be avoided based on current data but recent evidence from controlled studies suggests that anti-IgE or anti-tumor necrosis factor-(TNF-)alpha strategies might be of benefit in these patients. There is data that different phenotypes of therapy-resistant asthma might exist but little if any evidence to suggest a single phenotype of therapy-resistant asthma.

Adrenal Cortex Hormones↗
PubMed2005

Blockade of interleukin-13-mediated cell activation by a novel inhibitory antibody to human IL-13 receptor alpha1.

Interleukin-13 (IL-13) is a cytokine with a crucial role in the development of allergic asthma. The IL-13 receptor shares the IL-4Ralpha subunit with the IL-4R system, but contains as a specific component the IL-13Ralpha1 chain. Blocking signal release by IL-13 without affecting IL-4 function is a potentially interesting therapeutical option for the treatment of asthma. Employing genetic immunization, we generated a set of novel monoclonal antibodies to the IL-13Ralpha1 receptor that proved very specific and efficient inhibitors of human IL-13 activity. Receptor binding antibodies were identified by their specific reactivity with both human monocytes and a murine pro-B cell line overexpressing human IL-13Ralpha1 by flow cytometry and cell ELISA. A luciferase reporter cell system based on STAT6-mediated promoter activation in murine Ba/F3 cells was employed to screen the antibodies for IL-13 antagonistic properties. Inhibitory antibody effects were quantified by interference with IL-13-dependent proliferation of TF-1 cells. The capability of blocking IL-13-driven responses of primary, inflammation-relevant cells was tested by Western blot analysis of STAT6 tyrosine phosphorylation and expression of 15-lipoxygenase in monocytes from fresh blood. The most potent inhibitory antibody identified, GM1E7, inhibited IL-13-driven gene activation and cell proliferation in immune cell lines with IC(50) values in the low nanomolar range. Both short-term (STAT6 activation) and long-term (15-LO induction) responses of primary human blood cells to IL-13 were almost entirely blocked, whereas IL-4 effects remained virtually unaffected. GM1E7 is superior to available agents interfering with IL-13 activity in terms of specificity and efficiency and offers potential novel therapeutic perspectives for the treatment of allergic asthma.

Antibodies, Monoclonal↗
PubMed2005

Maternal serum concentrations of BDNF and depression in the perinatal period.

There is accumulating evidence that a deficiency in brain-derived neurotrophic factor (BDNF) plays a critical role in the pathophysiology of depression. This is in line with the postulate that low BDNF levels in serum are associated with depression. However, the regulation of maternal BDNF serum levels in the perinatal period, and its relationship to maternal depression is unknown. In this study, serum BDNF concentrations were measured in 40 pregnant (follow-up: 30th and 37th week of gestation, 1 week and 8 weeks after childbirth) and 40 non-pregnant women (20-40 years old). The Edinburgh Postnatal Depression Scale (EPDS) was assessed in all subjects at all time points. Maternal serum levels of BDNF were markedly decreased, both before and after childbirth (median: <30% of non-pregnant controls). BDNF correlated with decreased Serotonin (5-HT) levels in serum (r>0.6 and p<0.001 at all time points). In contrast, there was no association with altered estrogen, progesterone, dehydroepiandrosterone or cortisol concentrations in serum. There were significantly higher cortisol levels in cases of maternal depression (EPDS scores>9 points) than in cases without depression. There was a trend to a decrease of BDNF and 5-HT levels in cases of maternal depression (as compared to cases without depression), but this was not significant. In conclusion, we demonstrate that women display markedly decreased BDNF serum levels before and after childbirth. This phenomenon might reflect an increased risk for the development of mood disorders in the perinatal period. However, the individual serum concentration of BDNF alone did not predict maternal depression in our study.

Adult↗
PubMed2005

Differential expression of the granzymes A, K and M and perforin in human peripheral blood lymphocytes.

Granzymes (Gzm) are a group of serine proteases which are stored in the granules of cytotoxic lymphocytes. In humans, five granzymes have been characterized to date at the molecular level. While GzmA and GzmB have been extensively studied, little is known about GzmH, GzmK and GzmM. In this study, we describe the generation of mAbs against human GzmK and GzmM by genetic immunization. The obtained anti-GzmK and anti-GzmM mAbs are not cross-reactive with GzmA, GzmB, GzmM and GzmA, GzmB, GzmK, respectively, and show a granular staining pattern in human lymphocytes. Flow cytometric analysis of peripheral blood lymphocytes revealed that GzmA, GzmM and perforin show a similar distribution. They are expressed in almost all CD16+CD56+ NK cells, CD3+CD56+ NKT cells and gammadelta T cells as well as in 20-30% of all CD3+CD8+ TC cells. Surprisingly, GzmK was not detected in the highly cytotoxic CD16+CD56+ NK cells but was preferentially expressed in lymphocytes of the T cell lineage, staining 20% of CD3+CD8+ TC cells, 50% of CD3+CD56+ NKT cells and 40% of gammadelta T cells, as well as 60% of the small sub-population of CD56bright+ NK cells. Our data suggest that human granzymes are differentially expressed in distinct sub-populations of peripheral blood lymphocytes.

Antigens, CD↗
PubMed2005

The P2Y14 receptor of airway epithelial cells: coupling to intracellular Ca2+ and IL-8 secretion.

Uridine nucleotides and UDP-glucose are endogenous molecules, which are released into the extracellular environment in a lytic manner after cell damage, as well as by regulated nonlytic mechanisms. Recently, a UDP-glucose-specific G(i) protein-coupled P2Y receptor, namely P2Y(14), has been cloned. In this study, we demonstrated expression of the P2Y(14) mRNA in human lung epithelial cells and in the epithelial cell lines A549 and BEAS-2B. Evidence of functional expression of the P2Y(14) receptor in these cell lines was provided by calcium measurements after stimulation with uridine 5'-diphosphoglucose (UDP-glc). Experiments with pertussis toxin and the Ca(2+)-chelator EGTA revealed participation of pertussis toxin-sensitive G(i/o)-proteins in the mobilization of Ca(2+)-ions from intracellular stores by UDP-glc. Moreover, UDP-glc increased secretion of the potent neutrophil chemoattractant CXCL8/IL-8 in A549 and BEAS-2B cells in a pertussis toxin-sensitive manner. Moreover, reverse transcription and quantitative polymerase chain reaction revealed that UDP-glc modulated mRNA levels of IL-8/CXCL8. However, stimulation of A549 and BEAS-2B cells with UDP-glc neither modified basal nor cytokine-induced secretion of the CXC-chemokines CXCL9/MIG, CXCL10/IP-10, and CXCL11/I-TAC. In addition, UDP-glc did not affect proliferation of the two cell lines. In summary, our data provide evidence for a distinct physiologic role of P2Y(14) in the selective release of specific chemokines from human airway epithelial cells.

Calcium↗
PubMed2005

Differential expression of human granzymes A, B, and K in natural killer cells and during CD8+ T cell differentiation in peripheral blood.

NK cells and cytotoxic T lymphocytes can induce apoptosis in virus-infected and transformed target cells via the granule exocytosis pathway. The key components of the cytolytic granules are perforin and several serine esterases, termed granzymes. While the cellular distribution of human granzymes A (GrA) and B (GrB) has been well characterized much less is known about the expression pattern of human granzyme K (GrK). In this study GrA, GrB, and GrK expression was analyzed in human peripheral blood lymphocytes using flow cytometry. There was a distinct population of GrK expressing CD8+ T cells with a CD27+/CD28+/CCR5high/CCR7-/perforin-/low/IFN-gamma+ memory-like phenotype, while all CD56bright NK cells were also positive for GrK. In addition, GrK was also expressed in subpopulations of CD56+ T cells, CD4+ T cells, and TCRgammadelta+ T cells. In contrast, GrB was primarily expressed in CD56dim NK cells and differentiated memory CD8+ T cells with the CD27-/low/CD28-/low/CCR5-/low/CCR7-/CD11b+/perforinhigh phenotype. Only few CD8+ T cells expressed both GrB and GrK. GrA was found to be co-expressed in all GrB- and GrK-expressing T cells. Our findings suggest that granzyme expression during the differentiation process of memory CD8+ T cells might be as follows: GrA+/GrB-/GrK+ --> GrA+/GrB+/GrK+ --> GrA+/GrB+/GrK-.

CD11b Antigen↗
PubMed2005

Detection of soluble human granzyme K in vitro and in vivo.

Granzymes are serine proteases released from the granules of cytotoxic lymphocytes during the induction of apoptosis. To evaluate the physiologic role of human granzyme K (GzmK), we developed a sensitive ELISA which was shown to specifically detect human GzmK in its active as well as its inactive conformation. Analysis of the lysate of lymphokine-activated killer (LAK) cells by gel filtration revealed that GzmK seems to be complexed to proteoglycans within these cells. While the expression of GzmA and B by cytotoxic lymphocytes was strongly up-regulated in response to several activating stimuli, GzmK expression did not increase significantly above constitutive levels, indicating differential regulation of these granzymes. However, low levels of GzmK were detected in plasma samples of healthy volunteers, which were in the same range as levels of GzmA and B. Furthermore, circulating levels of GzmK as well as of GzmA and B were significantly elevated in patients suffering from viral infections. We conclude that GzmK protein is produced by cytotoxic cells, and just as GzmA and B it can be released in a soluble form into the extracellular space. Furthermore, our data suggest that despite a more restricted cellular expression pattern, GzmK seems to participate in immune responses against several viruses.

Enzyme-Linked Immunosorbent Assay↗
PubMed2005

What plays a role in the choice of inhaler device for asthma therapy?

Inhalation is the preferred route of delivery for anti-asthma drugs. However, in reality inhalers are often prescribed on an empirical basis rather than on evidence-based awareness. Asthma management guidelines also guide inhaler choice, but they offer non-specific advice regarding inhaler choice, are very long and complicated and not conducive to rapid assimilation by a busy GP. In addition, device selection criteria differ according to who you are asking (i.e. the inhalation technologist, the physician or the patient). The ideal inhaler should be small and have a guided sequence of inhalation, leading patients in a logical sequence of events through the inhalation manoeuvre. It should be breath-activated, releasing medication only when all prerequisites for successful inhalation are met. Most importantly, there should be flow-independent deposition of drug in the lungs and feedback on the successfully performed inhalation manoeuvre to reassure the patient that the drug has been successfully released from the inhaler. The ideal inhaler should also have a low intrinsic airflow resistance, making it suitable for use by patients who have a low inspiratory airflow (e.g. children and elderly patients). In order to check for compliance, the ideal inhaler should have an accurate dose counter which is linked to correct inhalation rather than simply to dose release, and patients should be able to use an identical inhaler device to deliver each of their different medications. Finally, from an environmental and cost-effectiveness point of view, the ideal inhaler should be refillable. Among the currently available dry powder inhalers the Novolizer device fulfils several characteristics of an ideal inhaler for the treatment of asthma and chronic obstructive pulmonary disease (COPD).

Anti-Asthmatic Agents↗
PubMed2004

Guidelines versus clinical practice--which therapy and which device?

Inhalation therapy delivers therapeutic agents directly into the lungs of patients with asthma, and is likely to remain the route of delivery of choice for the foreseeable future. The majority of patients with asthma suffer from mild intermittent to mild persistent disease for which regular low dose inhaled corticosteroids and on demand short-acting beta2-agonists have been recommended. These highly effective anti-asthma medications are readily available, and so in the future improvement in asthma therapy will most Likely derive from improvements in inhaler technology. Dry powder inhalers (DPIs) have many advantages compared to chlorofluorocarbon pressurised metered dose inhalers. Most notably, with DPIs patients no longer need to co-ordinate activation of the inhaler with inspiration. The Novolizer (VIATRIS, Germany) which is one of the latest developments in DPI technology offers a number of features required to increase the safety and efficacy of inhaled therapy. It is the first DPI to include an inspiratory trigger threshold, which helps to prevent sub-optimal dose administration. Repeated activation without inhalation is mechanically inhibited by an overdose prevention mechanism. In conclusion, there is good evidence that technically refined DPIs are more likely to advance inhaled anti-asthmatic therapy than newly developed inhaled drugs. This is important when inhalation therapy is considered not only for asthma but also for chronic obstructive pulmonary disease.

Anti-Asthmatic Agents↗